In the following discussion certain articles and methods will be described for background and introductory purposes. Nothing contained herein is to be construed as an “admission” of prior art. Applicant expressly reserves the right to demonstrate, where appropriate, that the articles and methods referenced herein do not constitute prior art under the applicable statutory provisions.
Anterior Gradient Homolog 2 (AGR2) encodes a 17 kDa protein that is highly conserved in vertebrates. In humans, enhanced AGR2 expression was first described in breast cancer, which was followed by similar observations in most human adenocarcinomas, including those derived from the esophagus, pancreas, lung, ovary, and prostate (see, e.g., Hao et al., Gastroenterology, 131:925-33 (2006); Lowe et al., PLoS ONE, 2:e323 (2007); Ramachandran et al., Cancer Res, 68:7811-18 (2008); Thompson and Weigel, Biochem Biophys Res Commun, 251:111-16 (1998); Zhang et al., Genes Chromosomes Cancer, 43:249-59 (2005); Fritzsche et al., Histology and Histopathology, 22:703-08 (2007); Zhu et al., Cancer Lett, 245:303-14 (2007); and Edgell et al., Clin Sci Lond, 118:717-25 (2010)). Although unpublished, it is also known that AGR2 expression is enhanced in colon and stomach adenocarcinoma. Papillary tumors of the thyroid also exhibit high AGR2 expression, and both in vitro and in vivo studies have demonstrated that AGR2 promotes tumor growth and metastasis (Wang et al., Cancer Res, 68:492-97 (2008); Ramachandran et al. (2008), supra; and Liu et al., Cancer Res, 65:3796-05 (2005)). In adenocarcinoma cell lines and nontransformed fibroblasts, AGR2 induces cell proliferation and anchorage-independent growth in soft agar, and human adenocarcinoma cell lines grown in vivo as mouse xenografts result in smaller tumors when AGR2 expression is reduced (Wang et al., (2008), supra; Ramachandran et al. (2008), supra).
Thus given the association of enhanced AGR2 expression with cell proliferation and a variety of cancers, it is of interest in the art to reduce AGR2 expression. The present invention provides methods and compositions that address this need.